Use of dideoxy nucleoside analogues in the treatment of viral infections

ABSTRACT

The present invention is directed to a method of treating hepatitis B viral infections in mammals comprising the administration of β-L-5-fluoro-2&#39;,3&#39;-dideoxycytidine and pharmaceutically acceptable derivatives thereof.

The present invention relates to nucleoside analogues and their use inmedicine. More specifically the invention is concerned with dideoxynucleoside analogues, pharmaceutical formulations thereof and the usethereof in the treatment of viral infections.

The only compounds currently approved for the treatment of conditionscaused by HIV are D-3'-azido-3'-deoxythymidine (AZT, zidovudine, BW509U) and β-D-2',3'-dideoxyinosine (ddI, didanosine) which has beenapproved for use in patients who are intolerant to AZT. Also,β-D-2',3'-dideoxycytidine (ddC) has received approval only incombination with AZT. The above compounds derived from physiologicallyimportant nucleosides have significant side-effect liability anddose-limiting toxicity. Additionally, resistance to AZT, ddC and ddI hasemerged (K. J. Connolly and S. M. Hammer, Antimicrob. Agent. Chemother.1992; 36, 245-254).

There is, in consequence, a continuing need to provide compounds whichare effective against HIV but with a concommitant significantly bettertherapeutic index (i.e. more selective).

The compounds mentioned above are all used in the form of their naturalenantiomers (D sugars). The corresponding unnatural enantiomers of AZT(L-AZT) and ddI (β-L-ddI) have been found to be inactive against HIV (J.Wengel et al. J. Org. Chem, 1991; 56, 3591-3594; and M. M. Mansuri etal. BioMed. Chem. Lett. 1991; 1, 65-68) whereas the unnatural enantiomerof ddC (β-L-ddC) was reported to be inactive or weakly active againstHIV (M. Okabe & al. J. Org. Chem. 1988; 54, 4780-4786 and M. M. Mansuri& al. Bio Med. Chem. Lett. 1991; 1, 65-68) with no mention ofselectivity. Furthermore, there has been no report in the literatureabout the activity of β-L-ddC against the Hepatitis B virus (HBV).

We have now found that, surprisingly, β-L-ddC, the unnatural(-)-enantiomer of ddC is active against HIV with unexpectedly highselectivity.

Furthermore, we have also found, unexpectedly, that β-L-ddC possessesexcellent activity against Hepatitis B virus.

Moreover, the 5-fluoro analogue of ddC (5F-ddC) has been described andtested in the form of its natural enantiomer (β-D-5F-ddC) and found tobe active against HIV (Kim et al., J. Med. Chem. 1987: 30, 862-866).However, its activity against HBV has not been reported.

We have found that the natural enantiomer of 5F-ddC (β-D-5F-ddC) isactive against against HBV.

In addition, there has been no reports of the activity of itscorresponding unnatural enantiomer (β-L-5F-ddC) against HIV or HBV.

We have also found, unexpectedly, that the unnatural enantiomer of5F-ddC (β-L-5F-ddC) possesses activity against HIV and HBV below itscytotoxic concentration.

SUMMARY OF THE INVENTION

There is thus provided, in a first aspect of the invention, the use ofthe (-)-enantiomer of ddC (β-L-ddC) and pharmaceutically acceptablederivatives thereof in the treatment of HIV infection.

There is also provided, in a second aspect of the invention, the use ofβ-L-ddC and pharmaceutically acceptable derivatives thereof in thetreatment of HBV infections.

There is further provided, in a third aspect of the invention, the useof β-D-5F-ddC and pharmaceutically acceptable derivatives thereof in thetreatment of HBV infections.

Furthermore, there is provided, in a fourth aspect of the invention, theuse of β-L-5F-ddC and pharmaceutically acceptable derivatives thereoffor the treatment of HIV infections.

There is also provided, in a fifth aspect of the invention, the use ofβ-L-5F-ddC and pharmaceutically acceptable derivatives thereof for thetreatment of HBV infections.

These compounds are represented by formula (I): ##STR1## wherein X ishydrogen or fluoro. The compounds of formula (I) are racemic mixtures ofthe two enantiomers of formulae (Ia) and (Ib): ##STR2##

The (-)-enantiomer of ddC has the absolute configuration of 1'S at thecarbon bearing the base and 4'R at the carbon bearing the CH₂ OH moiety.It has the absolute stereochemistry of the compound of formula (Ib) andthe chemical name of β-L-2',3'-dideoxycytidine or(1'S,4'R)-2',3'-dideoxycytidine (hereinafter Compound A). The(+)-enantiomer of 5F-ddC has the absolute stereochemistry of thecompound of formula (Ia) and the chemical name ofβ-D-5-fluoro-2',3'-dideoxycytosine (hereinafter Compound B).

The (-)-enantiomer of 5F-ddC has also the absolute stereochemistry ofthe compound of formula (Ib) and the chemical name ofβ-L-5-fluoro-2',3'-dideoxycytosine (hereinafter Compound C).

Preferably compound A or C are provided substantially free of thecorresponding (+)-enantiomer, that is to say no more than about 5% w/wof the (+)-enantiomer, preferably no more than about 2%, in particularless than about 1% w/w is present.

Preferably compound B is provided substantially free of thecorresponding (-)-enantiomer, that is to say no more than about 5% w/wof the (-)-enantiomer, preferably no more than about 2%, in particularless than about 1% w/w is present.

By "a pharmaceutically acceptable derivative" is meant anypharmaceutically acceptable salt, ester, or salt of such ester, ofcompound A, B or C or any other compound which, upon admistration to therecipient, is capable of providing (directly or indirectly) compound A,B or C or an antivirally active metabolite or residue thereof.

It will be appreciated by those skilled in the art that compound A, B orC may be modified to provide pharmaceutically acceptable derivativesthereof, at functional groups in both the base moiety and at thehydroxymethyl group of the oxathiolane ring. Modification at all suchfunctional groups are included within the scope of the invention.However of particular interest are pharmaceutically acceptablederivatives obtained by modification of the 2-hydroxymethyl group at4'-carbon of the sugar ring.

Preferred esters of compound A, B or C include the compounds in whichthe hydrogen of the 2-hydroxymethyl group is replaced by an acylfunction R--C(O)-- in which the non-carbonyl moiety R of the ester isselected from hydrogen, straight or branched chain alkyl (e.g. methyl,ethyl, n-propyl, t-butyl, n-butyl), alkoxyalkyl (e.g. methoxymethyl),aralkyl (e.g. benzyl), aryloxyalkyl (e.g. phenoxymethyl), aryl (e.g.phenyl optionally substituted by halogen, C₁₋₄ alkyl or C₁₋₄ alkoxy);sulphonate esters such as alkyl- or aralkylsulphonyl (e.g.methanesulphonyl); amino acid esters (e.g. L-valyl or L-isoleucyl) andmono-, di- or tri-phosphate esters.

With regard to the above described esters, unless otherwise specified,any alkyl moiety present advantageously contains 1 to 16 carbon atoms,particularly 1 to 4 carbon atoms. Any aryl moiety present in such estersadvantageously comprises a phenyl group.

In particular the esters may be a C₁₋₁₆ alkyl ester, an unsubstitutedbenzyl ester or a benzyl ester substituted by at least one halogen(bromine, chlorine, fluorine or iodine), C₁₋₆ alkyl, C₁₋₆ alkoxy, nitroor trifluoromethyl groups.

Pharmaceutically acceptable salts of the compound A, B or C includethose derived from pharmaceutically acceptable inorganic and organicacids and bases. Examples of suitable acids include hydrochloric,hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric,glycollic, lactic, salicylic, succinic, toleune-p-sulphonic, tartaric,acetic, citric, methanesulphonic, formic, benzoic, malonic,naphthalene-2-sulphonic and benzenesulphonic acids. Other acids such asoxalic, while not in themselves pharmaceutically acceptable, may beuseful as intermediates in obtaining the compounds of the invention andtheir pharmaceutically acceptable acid addition salts.

Salts derived from appropriate bases include alkali metal (e.g. sodium),alkaline earth metal (e.g. magnesium), ammonium and NR₄ + (where R isC₁₋₄ alkyl) salts.

References hereinafter to a compound according to the invention include,the compound A, B or C and their pharmaceutically acceptablederivatives.

The compounds of the invention either themselves possess antiviralactivity and/or are metabolizable to such compounds. In particular thesecompounds are effective in inhibiting the replication of retroviruses,including human retroviruses such as human immunodeficiency viruses(HIV's), the causative agents of AIDS.

There is thus provided as a further aspect of the invention compound A,B or C or a pharmaceutically acceptable derivative thereof for use as anactive therapeutic agent in particular as an antiviral agent, forexample in the treatment of retroviral infections or infections byviruses known to possess reverse transcriptase activity (such asHepatitis B virus).

In a further or alternative aspect there is provided a method for thetreatment of a viral infection, in particular an infection caused by aretrovirus such as HIV, or by a virus possessing retroviral activitysuch as HBV in a mammal including man comprising administration of aneffective amount of compound A, B or C or a pharmaceutically acceptablederivative thereof.

There is also provided in a further or alternative aspect use ofcompound A, B or C or a pharmaceutically acceptable derivative thereoffor the manufacture of a medicament for the treatment of a viralinfection.

The compounds of the invention are also useful in the treatment of HBVor of AIDS related conditions such as AIDS-related complex (ARC),progressive generalised lymphadenopathy (PGL), AIDS-related neurologicalconditions (such as dementia or tropical paraparesis), anti-HIV antibodypositive and HIV-positive conditions, Kaposi's sarcoma, thrombocytopeniapurpurea and associated opportunistic infections for examplePneumocystis carinii.

The compounds of the invention are also useful in the prevention ofprogression to clinical illness of individuals who are anti-HIV or HBVantibody or HIV-or HBV-antigen positive and in prophylaxis followingexposure to HIV or HBV.

The compound A, B or C or pharmaceutically acceptable derivativesthereof may also be used for the prevention of viral contamination ofphysiological fluids such as blood or semen in vitro.

It will be appreciated by those skilled in the art that reference hereinto treatment extends to prophylaxis as well as the treatment ofestablished infections or symptoms.

It will be further appreciated that the amount of a compound of theinvention required for use in treatment will vary not only with theparticular compound selected but also with the route of administration,the nature of the condition being treated and the age and condition ofthe patient and will be ultimately at the discretion of the attendantphysician or veterinarian. In general however a suitable dose will be inthe range of from about 0.1 to about 750 mg/kg of bodyweight per daypreferably in the range of 0.5 to 60 mg/kg/day, most preferably in therange of 1 to 20 mg/kg/day.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example as two,three, four or more sub-doses per day.

The compound is conveniently administered in unit dosage form; forexample containing 10 to 1500 mg, conveniently 20 to 1000 mg, mostconveniently 50 to 700 mg of active ingredient per unit dosage form.

Ideally the active ingredient should be administered to achieve peakplasma concentrations of the active compound of from about 1 to about 75μM, preferably about 2 to 50 μM, most preferably about 3 to about 30 μM.This may be achieved, for example, by the intravenous injection of a 0.1to 5% solution of the active ingredient, optionally in saline, or orallyadministered as a bolus containing about 1 to about 100 mg of the activeingredient. Desirable blood levels may be maintained by a continuousinfusion to provide about 0.01 to about 5.0 mg/kg/hour or byintermittent infusions containing about 0.4 to about 15 mg/kg of theactive ingredient.

While it is possible that, for use in therapy, a compound of theinvention may be administered as the raw chemical it is preferable topresent the active ingredient as a pharmaceutical formulation.

The invention thus further provided a pharmaceutical formulationcomprising compound A, B or C or a pharmaceutically acceptablederivative thereof together with one or more pharmaceutically acceptablecarriers therefor and, optionally, other therapeutic and/or prophylacticingredients. The carrier(s) must be `acceptable` in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

Pharmaceutical formulations include those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, sub-cutaneous and intravenous) administrationor in a form suitable for administration by inhalation or insufflation.The formulations may, where appropriate, be conveniently presented indiscrete dosage units and may be prepared by any of the methods wellknown in the art of pharmacy. All methods include the step of bringinginto association the active compound with liquid carriers or finelydivided solid carriers or both and then, if necessary, shaping theproduct into the desired formulation.

Pharmaceutical formulations suitable for oral administration mayconveniently be presented as discrete units such as capsules, cachets ortablets each containing a predetermined amount of the active ingredient;as a powder or granules; as a solution, a suspension or as an emulsion.The active ingredient may also be presented as a bolus, electuary orpaste. Tablets and capsules for oral administration may containconventional excipients such as binding agents, fillers, lubricants,disintegrants, or wetting agents. The tablets may be coated according tomethods well known in the art. Oral liquid preparations may be in theform of, for example, aqueous or oily suspensions, solutions, emulsions,syrups or elixirs, or may be presented as a dry product forreconstitution with water or other suitable vehicle before use. Suchliquid preparations may contain conventional additives such assuspending agents, emulsiying agents, non-aqueous vehicles (which mayinclude edible oils), or preservatives.

The compounds according to the invention may also be formulated forparenteral administration (e.g. by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The compositions may take suchforms as suspensions, solutions, or emulsions in oily or aqueousvehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilisation from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

For topical administration to the epidermis the compounds according tothe invention may be formulated as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also contain one or more emulsifying agents,stabilising agents, dispersing agents, suspending agents, thickeningagents, or colouring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising active ingredient in a flavoured base, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert base such as gelatin and glycerin or sucrose andacacia; and mouthwashes comprising the active ingredient in a suitableliquid carrier.

Pharmaceutical formulations suitable for rectal administration whereinthe carrier is a solid are most preferably presented as unit dosesuppositories. Suitable carriers include cocoa butter and othermaterials commonly used in the art, and the suppositories may beconveniently formed by admixture of the active compound with thesoftened or melted carrier(s) followed by chilling and shaping inmoulds.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

For intra-nasal administration the compounds of the invention may beused as a liquid spray or dispersible powder or in the form of drops.

Drops may be formulated with an aqueous or non-aqueous base alsocomprising one more more dispersing agents, solubilising agents orsuspending agents. Liquid sprays are conveniently delivered frompresurrised packs.

For administration by inhalation the compounds according to theinvention are conveniently delivered from an insufflator, nebuliser or apressurised pack or other convenient means of delivering an aerosolspray. Pressurised packs may comprise a suitable propellant such asdichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a presurrised aerosol the dosage unit may be determined byproviding a valve to deliver a metered amount.

Alternatively, for administration by inhalation or insufflation, thecompounds according to the invention may take the form of a dry powdercomposition, for example a powder mix of the compound and a suitablepowder base such as lactose or starch. The powder composition may bepresented in unit dosage form in, for example, capsules or cartridges ore.g. gelatin or blister packs from which the powder may be administeredwith the aid of an inhalator or insufflator.

When desired the above described formulations adapted to give sustainedrelease of the active ingredient may be employed.

The pharmaceutical compositions according to the invention may alsocontain other active ingredients such as antimicrobial agents, orpreservatives.

The compounds of the invention may also be used in combination withother therapeutic agents for example other antiinfective agents. Inparticular the compounds of the invention may be employed together withknown antiviral agents.

The invention thus provides, in a further aspect, a combinationcomprising the compound A, B or C or a physiologically acceptablederivative thereof together with another therapeutically active agent,in particular an antiviral agent.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above together with apharmaceutically acceptable carrier therefor comprise a further aspectof the invention.

Suitable therapeutic agents for use in such combinations include acyclicnucleosides such as acyclovir or ganciclovir, interferons such as α, βor γ-interferon, renal excretion inhibitors such as probenecid,nucleoside transport inhibitors such as dipyridamole, 1,3-oxathiolanenucleoside analogues, such as 3TC, 2',3'-dideoxynucleosides such as AZT,2',3'-dideoxyadenosine, 2',3'-dideoxyinosine, 2',3'-dideoxythymidine,2',3'-dideoxy-2'3'-didehydrothymidine and2',3'-dideoxy-2',3'-didehydrocytidine, FIAU, immunomodulators such asinterleukin II (IL2) and granulocyte macrophage colony stimulatingfactor (GM-CSF), erythropoetin, ampligen, thymomodulin, thymopentin,foscarnet, ribavirin, and inhibitors of HIV binding to CD4 receptorse.g. soluble CD4, CD4 fragments, CD4 hybrid molecules, glycosylationinhibitors such as 2-deoxy-D-glucose, castanospermine and1-deoxynojirimycin.

The individual components of such combinations may be administeredeither sequentially or simultaneously in separate or combinedpharmaceutical formulations.

When the compound A, B or C or a pharmaceutically acceptable derivativethereof is used in combination with a second therapeutic agent activeagainst the same virus the dose of each compound may be either the sameas or differ from that when the compound is used alone. Appropriatedoses will be readily appreciated by those skilled in the art.

The compound A, B or C and their pharmaceutically acceptable derivativesmay be prepared by any method known in the art for the preparation ofcompounds of analogous structure, for example as described ininternational publication No. WO 92/20969 which is herein incorporatedby reference.

It will be appreciated by those skilled in the art that for certain ofthe methods the desired stereochemistry of the compound A, B or C may beobtained either by commencing with an optically pure starting materialor by resolving the racemic mixture at any convenient stage in thesynthesis. In the case of all the processes the optically pure desiredproduct may be obtained by resolution of the end product of eachreaction.

EXAMPLE 1

Antiviral activity & Cytotoxicity

A) MT-4 Formazan assay

Antiviral activity was determined in MT-4 cells by inhibition offormazan conversion (Baba & al., (1987) Biochem. Biophys. Res. Commun.142, 128-134; Mossman (1983) J. Immun. Meth.; 65, 55-57).

B) Inhibition of Syncytium Formation Assay

C8166 cells were infected with HIV-1 (strain RF) at a moi of 1×10⁻³infectious units/cell and adsorbed at room temperature for 60 minutes.After adsorption, the cells were washed three times in growth medium.Aliquots of 10⁵ cells were added to each well of 24-well platescontaining serial dilutions of test compounds at final concentrations of50 μg/ml to 0.05 μg/ml in RPMI® 1640 growth medium. Untreated infectedcells and untreated uninfected cells were also included as controls. Theplates were incubated at 37° C./5% CO₂ for 3-4 days in humidifiedcontainers. The cells were examined daily for evidence of HIV-1 inducedsyncytium formation. The syncytia were quantified by reference to theuntreated infected controls, and the dose of compound required to reducethe cytopathic effect by 50% (ID₅₀) was calculated.

C) Cytotoxicity

The cytotoxicities of the compounds were determined in five CD4 celllines: H9, JM, CEM, C8166 and U937.

Compounds for test were serially diluted from 100 μg/ml to 0.3 μg/ml(final concentrations) in 96 well microtitre plates. 3.6×10⁴ cells wereinoculated into each well of the plates including drug-free controls.After incubation at 37° C. for 5 days, the viable cell count wasdetermined by removing a sample of cell suspension and counting trypanblue excluding cells in a haemocytometer.

Results are shown in Table 1.

D) Inhibition of Human Hepatitis B virus.

The method used for this test is described in detail in Korba et al.,Antiviral Research 15, 217-228 (1992) which is shortly described asfollows:

Hep G2 cells transfected with human hepatitis B virus genomic DNA(2.2.15 cells) were grown and maintained in RPMI-1640 culture mediumcontaining %5 foetal bovine serum, 2 mM glutamine and 50 μg/mlgentamicin sulphate, and checked routinely for G418 resistance. Culturesof 2.2.15 cells were grown to confluence in 24 well tissue cultureplates and maintained for 2 to 3 days in that condition prior to drugtreatment.

Drugs were dissolved in sterile water or sterile 50% DMSO in water atconcentrations 100-fold higher than the higher test concentration. Thesesolutions were diluted as needed in culture medium.

The culture medium on the confluent cells was changed 24 hours prior toexposure to test compounds. During the 10 day treatment, the culturemedium was changed daily. After 10 days of the treatment, the culturemedium was collected and frozen at -70° C. for HBV DNA analysis.

To analyse extracellular HBV DNA, 0.2 ml samples of culture medium wereincubated for 20 minutes at 25° C. in 1M NaOH/10× SSC (1× SSC is 0.15MNaCl/0.015M Sodium Citrate, pH 7.2) and then applied to nitrocellulosemembranes presoaked in 20× SSC. Filters were then rinsed in 2× SSC andbaked at 80° C. for 1 hour under vacuum.

A purified 3.2 kb EcoR1 HBV DNA fragment was labelled with [³² P]dCTP bynick translation and used as a probe to detect HBV DNA on the dot-blotby DNA hybridisation. After washing, the hybridised blot was dried and32P was quantified using an Ambis beta scanner.

Results are shown in Table 2.

                  TABLE 1                                                         ______________________________________                                        50% Antiviral Activity against HIV in μg/ml (μM)                                   Formazan       Syncytium Formation                                 Assay      Antiviral                                                                              Cytotoxicity                                                                            Antiviral                                                                            Cytotoxicity                             ______________________________________                                        AZT (natural)                                                                            0.0022    >1       0.002  >0.5                                        (0.0092)  (0.0084)                                                           A) β-L-ddC (-) 0.022 >100 0.014  >5                                      (unnatural) (0.1) (>474) (0.067) (>24)                                        B) β-D-5F-ddC (+) 0.145  10 0.0056 >0.5                                  (natural) (0.63)  (44) (0.02) (>2.2)                                          C) β-L-5F-ddC (-) 0.05   1 0.011 >0.5                                    (unnatural) (0.22) (4.4) (0.05) (>2.2)                                      ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        50% Antiviral Activity against HBV in μg/ml                                                   Hepatitis B Virus                                          Assay              Antiviral                                                                              Cytotoxicity                                      ______________________________________                                        AZT                                                                             A) β-L-ddC (-) (unnatural) 0.44 >10                                      B) β-D-5F-ddC (+) (natural) <10 >10                                      C) β-L-5F-ddC (-) (unnatural) <10 >10                                  ______________________________________                                    

We claim:
 1. A method for the treatment of hepatitis B viral infectionsin mammals comprising the step of administering a pharmaceuticallyeffective amount of a β-L enantiomer of formula (Ib): ##STR3## orpharmaceutically acceptable derivatives thereof.
 2. A method for thetreatment of hepatitis B viral infections in mammals comprising the stepof administering a pharmaceutically effective amount of a mixture of theβ-L-enantiomer of formula (Ib) and the β-D-enantiomer of formula (Ia):##STR4## wherein said mixture contains no more than about 5% w/w of theβ-D-enantiomer.
 3. The method according to claim 2 wherein said mixturecontains no more than about 2% w/w of the β-D-enantiomer.
 4. The methodaccording to claim 2 wherein said mixture contains no more than about 1%w/w of the β-D-enantiomer.
 5. The method according to claim 1, whereinsaid administration is carried out at a dose of about 0.1 to at least750 mg/kg of body weight per day.
 6. The method according to claim 5wherein said administration is carried out at a dose of about 0.5 to atleast 60 mg/kg of body weight per day.
 7. The method according to claim6, wherein said administration is carried out at a dose of about 1.0 toat least 20 mg/kg of body weight per day.
 8. The method according toclaim 1, wherein said enantiomer is administered in dosage unit form. 9.The method according to claim 8 wherein said enantiomer is administeredin dosage unit form in the amount of about 10 to 1500 mg.
 10. The methodaccording to claim 9 wherein said enantiomer is administered in dosageunit form in the amount of about 20 to 1000 mg.
 11. The method accordingto claim 10 wherein said enantiomer is administered in dosage unit formin the amount of about 50 to 700 mg.
 12. The method according to claim 5wherein said administration is carried out in admixture with apharmaceutically acceptable carrier.
 13. The method according to any oneof claims 6, 7, 9, 10 or 11 wherein said administration is carried outin admixture with a pharmaceutically acceptable carrier.
 14. The methodaccording to claim 8, wherein said administration is carried out inadmixture with a pharmaceutically acceptable carrier.
 15. The methodaccording to claim 12 or 14 wherein said administration is carried outwith another therapeutically active agent.
 16. The method according toclaim 13 wherein said administration is carried out with anothertherapeutically active agent.
 17. The method according to claim 15wherein said therapeutically active agent is an antiviral agent.
 18. Themethod according to claim 16 wherein said therapeutically active agentis an antiviral agent.
 19. The method according to claim 17 and 18wherein said antiviral agent is AZT.
 20. The method according to claim18 wherein said antiviral agent is (-)-2'-deoxy-3'-thiacytidine.
 21. Thecompound, β-L-5-fluoro-2',3'-dideoxycytidine, and pharmaceuticallyacceptable derivatives thereof.
 22. A mixture ofβ-L-5-fluoro-2',3'-dideoxycytidine andβ-D-5-fluoro-2',3'-dideoxycytidine wherein the β-D-enantiomer is presentin an amount of no more than about 5% w/w.
 23. The mixture according toclaim 22 wherein the β-D-enantiomer is present in an amount of no morethan about 2% w/w.
 24. The mixture according to claim 22 wherein theβ-D-enantiomer is present in an amount of no more than about 1% w/w. 25.A pharmaceutical composition comprising a therapeutically effectiveamount of the compound of claim 21 in combination with apharmaceutically acceptable additive, carrier or excipient.
 26. Apharmaceutical composition comprising a therapeutically effective amountof the mixture of any of claims 22, 23 or 24 in combination with apharmaceutically acceptable additive, carrier or excipient.
 27. Thecompound 1-(2,3-Dideoxy-beta-L-ribofuranosyl)-5-fluorocytosine.
 28. Apharmaceutical composition comprising a therapeutically effective amountof the compound 1-(2,3-Dideoxy-beta-L-ribofuranosyl)-5-fluorocytosine incombination with a pharmaceutically acceptable additive, carrier orexcipient.
 29. A method of treating an HBV infection in a patientcomprising administering to said patient a therapeutically effectiveamount of the compound1-(2,3-Dideoxy-beta-L-ribofuranosyl)-5-fluorocytosine.